ZBP1 promotes inflammatory responses downstream of TLR3/TLR4 via timely delivery of RIPK1 to TRIF.
ZBP1 promotes inflammatory responses downstream of TLR3/TLR4 via timely delivery of RIPK1 to TRIF.
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ZBP1通过及时将RIPK1递送至TRIF来促进TLR3/TLR4下游的炎症反应。
DOI：
10.1073/pnas.2113872119
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发表时间：
2022-06-14
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
While ZBP1 is well documented to drive cell death in response to viruses, its role in the context of Toll-like receptor (TLR)–mediated immune activation remains less defined. Here, we show that ZBP1 promotes inflammation in response to bacterial lipopolysaccharide (LPS) or double-stranded RNA (dsRNA). In a dose dependent manner, ZBP1 promotes the recruitment of RIPK1 to the TLR3/4 adaptor TRIF, activating downstream inflammatory signaling. ZBP1 plays a crucial role in TRIF-dependent responses in vivo, as Zbp1−/− mice exhibited resistance to LPS-induced hypothermia and attenuated inflammatory responses to dsRNA. Our findings suggest that ZBP1 plays a synergistic role in the immune response by driving inflammation downstream of TLRs in response to bacterial and viral components. ZBP1 is widely recognized as a mediator of cell death for its role in initiating necroptotic, apoptotic, and pyroptotic cell death pathways in response to diverse pathogenic infection. Herein, we characterize an unanticipated role for ZBP1 in promoting inflammatory responses to bacterial lipopolysaccharide (LPS) or double-stranded RNA (dsRNA). In response to both stimuli, ZBP1 promotes the timely delivery of RIPK1 to the Toll-like receptor (TLR)3/4 adaptor TRIF and M1-ubiquitination of RIPK1, which sustains activation of inflammatory signaling cascades downstream of RIPK1. Strikingly, ZBP1-mediated regulation of these pathways is important in vivo, as Zbp1−/− mice exhibited resistance to LPS-induced septic shock, revealed by prolonged survival and delayed onset of hypothermia due to decreased inflammatory responses and subsequent cell death. Further findings revealed that ZBP1 promotes sustained inflammatory responses by mediating the kinetics of proinflammatory “TRIFosome” complex formation, thus having a profound impact downstream of TLR activation. Given the well-characterized role of ZBP1 as a viral sensor, our results exemplify previously unappreciated crosstalk between the pathways that regulate host responses to bacteria and viruses, with ZBP1 acting as a crucial bridge between the two.
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影响因子：
30.3
作者：
Nogusa S;Thapa RJ;Dillon CP;Liedmann S;Oguin TH 3rd;Ingram JP;Rodriguez DA;Kosoff R;Sharma S;Sturm O;Verbist K;Gough PJ;Bertin J;Hartmann BM;Sealfon SC;Kaiser WJ;Mocarski ES;López CB;Thomas PG;Oberst A;Green DR;Balachandran S
通讯作者：
Balachandran S
DOI：
10.4049/jimmunol.1701229
发表时间：
2018-01-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
O'Donnell JA;Lehman J;Roderick JE;Martinez-Marin D;Zelic M;Doran C;Hermance N;Lyle S;Pasparakis M;Fitzgerald KA;Marshak-Rothstein A;Kelliher MA
通讯作者：
Kelliher MA
影响因子：
4.4
作者：
Gowen, Brian B.;Wong, Min-Hui;Sidwell, Robert W.
通讯作者：
Sidwell, Robert W.
通过TAK1介导的磷酸化来调节RIPK1激活，决定了凋亡和坏死性。
影响因子：
16.6
作者：
Geng J;Ito Y;Shi L;Amin P;Chu J;Ouchida AT;Mookhtiar AK;Zhao H;Xu D;Shan B;Najafov A;Gao G;Akira S;Yuan J
通讯作者：
Yuan J
DOI：
10.4049/jimmunol.181.9.6427
发表时间：
2008-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kaiser WJ;Upton JW;Mocarski ES
通讯作者：
Mocarski ES